Monoacylglycerol lipase

Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein that, in humans, is encoded by the MGLLgene.[1][2][3] MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.[2][4]

Function

Monoacylglycerollipase functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.[5]

Monoacylglycerol lipase is a key enzyme in the hydrolysis of the endocannabinoid2-arachidonoylglycerol (2-AG).[6][7] It converts monoacylglycerols to the free fatty acid and glycerol. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% (ABHD6 and ABHD12 are responsible for ~4% and ~9%, respectively, of the remainder),[8][9] and this in vitro estimate has been confirmed in vivo by the selective MAGL inhibitor JZL184.[10] Chronic inactivation of MAGL results in massive (>10-fold) elevations of brain 2-AG in mice, along with marked compensatory downregulation of CB1 receptors in selective brain areas.[11]

Inhibitors and assay

The enzyme was reported to be inhibited by URB754; however this inhibitor has subsequently been shown to be inactive and its reported activity due to contamination.[12] While the compound N-arachidonoyl maleimide (NAM) inhibits MAGL,[13] NAM is not selective due to its chemically reactive maleimidefunctional group, which can also react with other thiol-containing small molecules and proteins (e.g., glutathione).

JZL184 is the first efficacious and selective inhibitor of MAGL that can elevate brain 2-AG levels in vivo.[10] JZL184 has >300-fold selectivity for MAGL over other brain serine hydrolases, including FAAH.

MAGL activity is commonly detected by measuring free fatty acid release from a monoacylglycerol substrate using a liquid chromatographymass spectrometry system or the radiolabelled substrate 2-oleoyl-[3H]-glycerol.

Reaction

Reaction catalyzed by MGLL, in which a free fatty acid (FFA) is released from a monoacylglycerol (MAG).